Much of what we know about poxvirus innate immune evasion comes from work with the prototype orthopoxvirus, vaccinia virus (VACV). However, it is becoming clear that what we know for VACV is not always true for other poxviruses. The example we have been working on is monkeypox virus (MPXV). VACV has an E3L gene, which is essential for interferon-resistance, both in cells in culture and in the animal model. Despite being highly pathogenic, MPXV is missing 37 residues from the N-terminus of its E3 homologue. Thus, it is surprising that MPXV is as pathogenic as it is, despite missing this essential region of the E3 innate immune evasion protein. We have shown that while the lack of an N-terminal innate immune evasion domain in MPXV allows the virus to be sensed by the host, MPXV has evolved at least two apparently independent mechanisms to overcome the effects of being sensed in cells. The goals of this research are to understand how this unique human pathogen is sensed in infected cells and how it has evolved to counter the effects of sensing. Loss of this innate immune evasion domain makes vaccination against MPXV problematic. The final goal of this project is to develop a vaccine that can safely protect against MPXV infection.